Pain is an unpleasant sensory experience associated with actual or potential tissue damage. Thus, pain is the most common symptom of various injuries and diseases. There exist different classifications of pain, for example, nociceptive pain, inflammatory pain associated with tissue damage and the infiltration of immune cells, and pathological pain, which is a disease state caused by damage to the nervous system (i.e., neuropathic pain) or by its abnormal function (dysfunctional pain, as in fibromyalgia, irritable bowel syndrome, tension type headache, etc.). Pain is usually transitory, lasting only until the noxious stimulus is removed or the underlying damage or pathology has healed, but some painful conditions, such as rheumatoid arthritis, peripheral neuropathy, cancer and idiopathic pain (pain that persists after the trauma or pathology has healed, or that arises without any apparent cause), may persist for years. Pain that lasts a long time is called chronic, and pain that resolves quickly is called acute. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset, the two most commonly used markers being 3 months and 6 months since the onset of pain (Turk, Okifuji, Pain terms and taxonomies of pain; In: Bonica, Loeser, Chapman, Turk, Butler, Bonica's management of pain. Hagerstown: Lippincott Williams & Wilkins, 2001), though some theorists and researchers have placed the transition from acute to chronic pain at 12 months (Spanswick, Main, Pain management: an interdisciplinary approach. Edinburgh: Churchill Livingstone, 2000). Others apply “acute” to pain that lasts less than 30 days, “chronic” to pain of more than six months' duration, and “subacute” to pain that lasts from one to six months (Thienhaus, Cole, Classification of pain. In: Weiner, Pain management: a practical guide for clinicians. Boca Raton: CRC Press, 2002). A popular alternative definition of chronic pain, involving no arbitrarily fixed durations, is “pain that extends beyond the expected period of healing” (Turk, Okifuji, 2001, Pain terms and taxonomies. In Loeser, Butler, Chapman, et al. Bonica's management of pain, Lippincott Williams&Wilkins. ISBN 0-683-30462-3). Chronic pain may be classified as cancer pain or benign (Thienhaus, Cole, 2002, Classification of pain. In Weiner, Pain management: A practical guide for clinicians, American Academy of Pain Management, ISBN 0-8493-0926-3).
Pain sensation is conveyed to the brain by sensory neurons which are also called nociceptors. Nociceptors are considered polymodal since they may respond to multiple forms of noxious or intense stimuli, such as heat, mechanical, and chemical stimuli. Sensory afferent fibers of nociceptors are heterogeneous in many aspects. For example, sensory nerves are classified as Aα, -β, -δ and C-fibers according to their diameter and degree of myelination. Then, sensory inputs from the periphery are processed and conveyed to higher brain regions by complex circuits involving excitatory and inhibitory interneurons within the spinal cord (Basbaum et al., 2009; Todd, 2010). The balance between excitation and inhibition is crucial for maintenance of normal sensory function, and dysfunction of these circuits leads to the development of pain such as inflammatory and neuropathic pain.
Treatment of pain includes the use of local anesthetics, which block neuronal transmission and affect sensation as well as pain, and analgesics, which relieve pain and additionally may interfere with the activity of chemical mediators of inflammation. Acute pain is usually managed with medications such as analgesics and anesthetics. Management of chronic pain, however, is much more difficult.
The effectiveness of analgesics relies on how they are able to block the nerve messages that are sent by the pain receptors to the brain. They further have an effect on the body temperature to increase it (known as fever) or decrease it. Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (para-acetylaminophenol, also known as acetaminophen or simply APAP), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, and opioid drugs such as morphine and opium.
The exact mechanism of action of paracetamol/acetaminophen is uncertain, but it appears to act centrally rather than peripherally (in the brain rather than in the nerve endings). Aspirin and the other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases, leading to a decrease in prostaglandin production. This reduces pain and also inflammation (in contrast to paracetamol and the opioids). Paracetamol has few side effects and is regarded as safe, although intake above the recommended dose can lead to liver damage, which can be severe and life-threatening, and occasionally kidney damage. NSAIDs predispose to peptic ulcers, renal failure, allergic reactions, and occasionally hearing loss, and can increase the risk of hemorrhage by affecting platelet function. The use of aspirin in children under 16 suffering from viral illness has been linked to Reye's syndrome, a rare but severe liver disorder. Morphine, the archetypal opioid, and various other substances (e.g., codeine, oxycodone, hydrocodone, dihydromorphine, pethidine) all exert a similar influence on the cerebral opioid receptor system. Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils) and seizures (tramadol), but there is no dose ceiling in patients who accumulate tolerance.
The analgesic choice is also determined by the type of pain: for neuropathic pain, traditional analgesics are less effective, and there is often benefit from classes of drugs that are not normally considered analgesics, such as tricyclic antidepressants and anticonvulsants. Tricyclic antidepressants, especially amitriptyline, have been shown to improve treatment of pain in what appears to be a central manner. Nefopam is used in Europe for pain relief with concurrent opioids. The exact mechanism of carbamazepine, gabapentin and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with differing degrees of success. Anticonvulsants are most commonly used for neuropathic pain as their mechanism of action tends to inhibit pain sensation.
However, certain combination analgesic products can result in significant adverse events, including accidental overdoses, most often due to confusion which arises from the multiple (and often non-acting) components of these combinations (Murnion, Combination analgesics in adults. Australian Prescriber (33):113-5. See Worldwide Website: australianprescriber.com/magazine/33/4/113/5).
Inadequate treatment of pain is widespread throughout surgical wards, intensive care units, accident and emergency departments, in general practice, in the management of all forms of chronic pain including cancer pain, and in end of life care. This neglect is extended to all ages, from neonates to the frail elderly. Improved treatments of pain are highly requested by patients, in particular when considering neuropathic, inflammatory and/or chronic pain for which treatment remains incomplete whatever the selected known analgesic molecule.